Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization.

As an autoimmune disease, up to 73% of patients with primary biliary cholangitis (PBC) have a combination of extrahepatic autoimmune diseases (EHAIDs); however, the causal relationship between PBC and EHAIDs is unclear. The genome-wide association analyses provided 14 GWAS data for PBC and EHAIDs, and bidirectional, two-sample MR analyses were performed to examine the relationship between PBC and EHAIDs. The analysis using MR provides a strong and meaningful estimation of the bidirectional correlation between PBC and 7 EHAIDs: rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, autoimmune hypothyroidism, inflammatory bowel disease and ulcerative colitis of its types. In addition, PBC increases the risk of autoimmune thyroid diseases such as autoimmune hyperthyroidism and Graves' disease, as well as multiple sclerosis and psoriasis. Additionally, PBC is identified as a risk factor for Crohn's disease and Celiac disease. Based on genetic evidence, there may be connections between PBC and specific EHAIDs: not all coexisting EHAIDs induce PBC, and vice versa. This underscores the significance of prioritizing PBC in clinical practice. Additionally, if any liver function abnormalities are observed during treatment or with EHAIDs, it is crucial to consider the possibility of comorbid PBC.

Prevalence and effect on prognosis of sarcopenia in patients with primary biliary cholangitis.

Background: Sarcopenia adversely affects the treatment outcomes in Cirrhosis and NAFLD. However, such research is limited in primary biliary cholangitis (PBC) patients. This study was performed to examine the prevalence of sarcopenia and its impact on PBC patients' prognoses. Methods: This study enrolled confirmed PBC patients who had an abdominal CT scan. Sarcopenia was determined by the L3-skeletal muscle index with a Chinese population-based cut-off value. Laboratory test values and liver stiffness measurements values were obtained from the electronic medical records. Results: In total, 174 PBC patients with a median age of 54 (IQR, 48, 62) years old, were enrolled. 45 (25.9%) patients among them were diagnosed with sarcopenia. Univariate and multivariate logistic regression results illustrated that male gender (OR = 9.152, 95%CI = 3.131-26.751, p < 0.001) and LSM ≥ 12.8 kPa (OR = 4.539, 95%CI = 1.651, 12.478, p = 0.003) were the independent risk factors of sarcopenia in PBC patients. In the prognosis analysis, sarcopenia was determined as a risk factor for indicating adverse events in PBC patients (HR = 4.058, 95%CI = 1.955-8.424, p < 0.001) by Cox proportional hazards regression. Conclusion: The current findings illustrate that comprehensive evaluation and management of sarcopenia may contribute to the improvement of treatment outcomes and life quality of PBC patients.

Causal associations between gut microbiota and Cholestatic liver diseases: a Mendelian randomization study.

Background: The etiological factors of Cholestatic Liver Diseases especially primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are not fully illustrated. It has been reported in previous observational studies that gut microbiota are associated with cholestatic liver diseases. However, there is uncertainty regarding the causality of this association. By using Mendelian randomization, this study aimed to examine the causal impact of gut microbiota on cholestatic liver diseases. Methods: From large-scale genome-wide association studies, genetic instruments for each gut microbiota taxa as well as primary biliary cholangitis and primary sclerosing cholangitis were developed. Subsequently, we conducted a two-sample Mendelian randomization analysis, supplemented by multiple post hoc sensitivity analyses. Additionally, we performed reverse MR analyses to investigate the possibility of the reverse causal association. Result: This two-sample MR study indicated that the order Bacillales, family Peptostreptococcaceae, family Ruminococcaceae, genus Anaerotruncu was associated with a decreased risk of developing PBC, and that order Selenomonadales, family Bifidobacteriaceae may be factors that increase the risk of PBC. On the other hand, we also identified order Selenomonadales, family Rhodospirillaceae, and genus RuminococcaceaeUCG013 were positively associated with PSC. The order Actinomycetales, family Actinomycetaceae, genus Actinomyces, genus Alloprevotella, genus Barnesiella, and genus Peptococcus were found negative associations with the risk of PSC. The reverse MR analysis demonstrated no statistically significant relationship between PBC, PSC and these specific gut microbial taxa. Conclusion: Our findings offered novel evidence that the abundance of particular bacteria contributes to the risk of PBC and PSC, which may contribute to more effective approaches to PBC and PSC therapy and prevention.

Epigenetic silencing of miR-144/451a cluster contributes to HCC progression via paracrine HGF/MIF-mediated TAM remodeling.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is among the malignancies with the highest mortality. The key regulators and their interactive network in HCC pathogenesis remain unclear. Along with genetic mutations, aberrant epigenetic paradigms, including deregulated microRNAs (miRNAs), exert profound impacts on hepatocyte transformation and tumor microenvironment remodeling; however, the underlying mechanisms are largely uncharacterized. METHODS: We performed RNA sequencing on HCC specimens and bioinformatic analyses to identify tumor-associated miRNAs. The miRNA functional targets and their effects on tumor-infiltrating immune cells were investigated. The upstream events, particularly the epigenetic mechanisms responsible for miRNA deregulation in HCC, were explored. RESULTS: The miR-144/miR-451a cluster was downregulated in HCC and predicted a better HCC patient prognosis. These miRNAs promoted macrophage M1 polarization and antitumor activity by targeting hepatocyte growth factor (HGF) and macrophage migration inhibitory factor (MIF). The miR-144/miR-451a cluster and EZH2, the catalytic subunit of polycomb repressive complex (PRC2), formed a feedback circuit in which miR-144 targeted EZH2 and PRC2 epigenetically repressed the miRNA genes via histone H3K27 methylation of the promoter. The miRNA cluster was coordinately silenced by distal enhancer hypermethylation, disrupting chromatin loop formation and enhancer-promoter interactions. Clinical examinations indicated that methylation of this chromatin region is a potential HCC biomarker. CONCLUSIONS: Our study revealed novel mechanisms underlying miR-144/miR-451a cluster deregulation and the crosstalk between malignant cells and tumor-associated macrophages (TAMs) in HCC, providing new insights into HCC pathogenesis and diagnostic strategies.

Effects of karanjin on dimethylhydrazine induced colon carcinoma and aberrant crypt foci are facilitated by alteration of the p53/Bcl2/BAX pathway for apoptosis.

We investigated the effects of karanjin on dimethylhydrazine (DMH) induced colon cancer in rats. Male Wistar rats were injected with DMH followed by dextran sodium sulfate in drinking water for 7 days. Karanjin at doses of 50,100 and 200 mg/kg was administered orally for 18 weeks. Colon tissues were investigated using TUNEL analysis of apoptosis; histopathological assessment including number of aberrant crypt foci (ACF); immunohistochemical staining for Bcl-2-associated X protein (BAX), B-cell lymphoma 2 (Bcl2), p53 and proliferating cell nuclear antigen (PCNA); and antioxidant assay in vivo. We found that treatment with karanjin inhibited formation of ACF in the colon mucosa and reduced colon lesions. Karanjin treatment also increased the antioxidants, catalase, glutathione and superoxide dismutase. Immunostaining showed that karanjin treatment reduced BAX, p53 and PCNA levels and increased Bcl2 expression. The TUNEL assay revealed that karanjin induced apoptosis in the colon mucosa. Our findings suggest that karanjin can ameliorate colon carcinogenesis in rats by regulating BAX, Bcl2 and p53 pathways.

Analysis of the clinical efficacy of liver resection combined with adjuvant microwave coagulation for patients with hepatocellular carcinoma.

BACKGROUND: Liver resection has been widely applied as a curative measure in the treatment of hepatocellular carcinoma (HCC) patients. However, the high rate of postoperative recurrence observed following liver resection proposes a problem, the solution for which is yet to be well established. Microwave coagulation is a therapy that was recently proposed as an adjuvant tool. In this study, we intended to evaluate the effectiveness of microwave coagulation as an auxiliary therapeutic method for patients undergoing liver resection. METHODS: A total of 236 consecutive patients classified as Barcelona Clinic Liver Cancer (BCLC) stage A who had only one tumor were enrolled in this retrospective study, regardless of tumor size. Survival analyses were performed using the Kaplan-Meier method, and the statistical differences between patients who underwent liver resection with and without adjuvant microwave coagulation were examined by the log-rank test. To investigate the prognostic factors for OS, we carried out univariate and multivariate Cox regression analyses. RESULTS: Based on the Kaplan-Meier curves, patients who underwent surgical resection with intraoperative adjuvant microwave coagulator had prolonged recurrence-free survival time and showed better overall survival (OS) than those who underwent surgical resection alone, with OS at 1, 3, and 5 years of 77.8%, 33.2%, 12.6% vs. 58.2%, 15.5%, 9.7%, respectively (log-rank P<0.001). The univariate and multivariate analyses demonstrated that tumor size, albumin, bilirubin, Child-Pugh score, and treatment method had significant prognostic power for both PFS and OS. According to the subgroup analyses based on the tumor size, there were significant differences in PFS and OS among overall subsets between the liver resection with adjuvant microwave coagulator and liver resection only groups. CONCLUSIONS: Liver resection combined with intraoperative adjuvant microwave coagulation had a better prognostic performance than treatment with liver resection alone. Adjuvant microwave coagulation should be suggested as an alternative treatment modality for BCLC stage A patients with a single tumor, regardless of its size.

Identifying optimal candidates for liver resection or transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma.

BACKGROUND: Recommended as the first-line treatment for advanced unresectable hepatocellular carcinoma (HCC), sorafenib has been shown to prolong median overall survival (OS) for patients. However, advanced HCC sees high heterogeneity across patient groups. Recently, a growing number of studies have indicated surgical resection and transarterial chemoembolisation (TACE) to perform well in patients with portal vein tumor thrombosis (PVTT). The aim of this study was to compare the outcomes of liver resection and TACE and to identify prognostic factors related to OS for BCLC stage C patients with performance status (PS) 1 who have a single tumor but no vascular invasion or extrahepatic spread. METHODS: A total of 323 consecutive patients in BCLC stage C with PS 1 who had only one tumor and no vascular invasion or extrahepatic spread were enrolled in this retrospective study, regardless of tumor size. Survival analyses were performed using the Kaplan-Meier analysis, and statistical differences between the TACE and sorafenib groups were examined by the log-rank test. Univariate and multivariate Cox regression analyses were performed to investigate the prognostic factors for OS. RESULTS: Based on the Kaplan-Meier curves, patients treated with surgical resection showed a better OS than those who underwent TACE, with OS at 1, 3, and 5 years (85.7%, 48.8%, and 33.3% vs. 66.6%, 21.8%, and 13.4%, respectively; log-rank P<0.001). Univariate and multivariate analyses demonstrated that tumor size, albumin, bilirubin, Child-Pugh score, and treatment method were significant prognostic factors for OS. According to the subgroup analyses based on tumor size, there were significant differences in OS among overall subsets between patients who underwent hepatectomy and those who underwent TACE therapy. CONCLUSIONS: Liver resection had a better prognostic performance than TACE and should be put forward as an alternative treatment modality to TACE for BCLC stage C patients with PS 1 who have a single tumor and no vascular invasion or extrahepatic spread.

Identifying optimal candidates of transarterial chemoembolization (TACE) vs. sorafenib in patients with unresectable hepatocellular carcinoma.

BACKGROUND: Sorafenib has been recommended as the first-line treatment and shown to prolong median overall survival (OS) of patients with advanced unresectable hepatocellular carcinoma (HCC). Recently, a growing amount of research has supported the application of transarterial chemoembolization (TACE) in patients with advanced-stage HCC. The aim of this study was to compare the outcomes of TACE and sorafenib and identify the prognostic factors related to OS for Barcelona Clinic Liver Cancer (BCLC) stage C patients with PS 1 but without vascular invasion or extrahepatic spread. METHODS: A total of 323 consecutive patients in BCLC stage C with PS 1 but without vascular invasion or extrahepatic spread were enrolled in this retrospective study. Survival analyses were performed using the Kaplan-Meier analysis, and the statistical differences between the TACE and sorafenib groups were examined by the log-rank test. Univariate and multivariate Cox regression analyses were performed to investigate the prognostic factors for OS. RESULTS: Based on the Kaplan-Meier curves, patients treated with TACE showed a better OS than those undergoing sorafenib, with respective OS at 1, 3, and 5 years (67.7%, 41.5%, 23.2% vs. 55.6%, 29.6%, 4.8%; log-rank P=0.002). The univariate analysis indicated that tumor size, tumor number, and treatment method, along with platelet (PLT), white blood cell (WBC), and α-fetoprotein (AFP) count, were associated with OS. The multivariate analysis demonstrated that tumor size, tumor number, and treatment method were significant prognostic factors for OS. According to the subgroups analyses based on the tumor size and tumor number, there were significant differences in OS among overall subsets between TACE and sorafenib therapy. CONCLUSIONS: TACE provided better prognostic performance than sorafenib and should be suggested as an alternative treatment modality to sorafenib for BCLC stage C patients with PS 1 but without vascular invasion or extrahepatic spread.

Comparison between Child-Pugh Score and albumin-bilirubin grade in patients treated with the combination therapy of transarterial chemoembolization and sorafenib for hepatocellular carcinoma.

BACKGROUND: Albumin-Bilirubin (ALBI) grade has been proposed for the evaluation of liver function in hepatocellular carcinoma (HCC). The combination therapy of transarterial chemoembolization (TACE) and sorafenib is widely used for HCC patients with preserved liver function; our study aimed to investigate and compare the discriminating values of ALBI grade and Child-Pugh score in overall survival (OS). METHODS: A total of 173 HCC patients with preserved liver function (Child-Pugh A) were enrolled. The prognostic values of OS for ALBI grade and Child-Pugh score were separately investigated. RESULTS: In multivariate analyses, both ALBI grade and Child-Pugh score could significantly stratify the patients with different OS [adjusted hazard ratio (HR) 2.15 and 1.48, P<0.001 and P=0.035 for ALBI grade and Child-Pugh score]. In addition, time-dependent ROC analysis demonstrated that the ALBI grade had a better discriminatory ability than Child-Pugh score in predicting survival, especially for long-term outcomes. According to the subgroup analyses, the ALBI grade remained significant in more patient subsets and was more consistent than Child-Pugh score for the prediction of OS. CONCLUSIONS: ALBI grade was better than Child-Pugh score in stratifying prognosis for HCC patients with preserved liver function (Child-Pugh A) and treated by the combination therapy of TACE and sorafenib.